Certain pyridyl salicylic acid derivatives

ABSTRACT

NEW SALICYCLIC ACID COMPOUNDS, PARTICULARLY 5-(HETEROCYCLIC)-SALICYCLIC ACID DERIVATIVES AND PROCESS FOR THEIR PREPARATION ARE CLAIMED. THE NEW 5-(HETEROCYCLIC)SALICYCLIC ACID COMPOUNDS DESCRIBED HAVE ANIT-INFLAMMATORY, ANTI-PYRETIC AND ANALGESIC ACTIVITY.

U te S ate Patent Q iw ABSTRACT OF THE DISCLOSURE New salicylic acid compounds, particularly S-(heterocyclic)-salicylic acid derivatives and process for their preparation are claimed. The new S-(heterocyclic)salicylic acid compounds described have anti-inflammatory, anti-pyretic and analgesic activity.

BACKGROUND OF THE INVENTION The development of anti-inflammatory compounds in the past two decades has seen the growth of a great many new drugs. Most of these have been steroids of the 11- oxygenated pregnane series. These, while highly effective, have the drawback of causing many side effects. There is a need in the market for equally effective compounds of much simpler structure and having less side effects.

SUMMARY OF THE INVENTION This invention relates to new salicylic acid compounds and processes for producing the same, particularly the 5-(heterocyclic)-salicylic acid derivatives. These compounds are useful in that. they have anti-inflammatory activity and are effective in the prevention and inhibition of edema and granuloma tissue formation. In addition, some of them have a useful degree of ,anti-pyretic and analgesic activity.

DESCRIPTION AND PREFERRED EMBODIMENTS This invention relates to new heterocyclic phenyl conipounds and to processes for producing the same. More specifically, it relates to 5-(heterocyclic)-salicylic acid compounds (2-hydroxy-5-heterocyclic benzoic acids). Still R2 coon wherein:

is a 6-membered ring structure containing from 1-3 hetero atoms or a S-mernbered ring structure containing from 1-4 hetero atoms. The hetero atoms are either nitrogen, sulphur, or oxygen;

more specifically, this invention relates to compounds having the following general formula:

Patented Jan. 26, 1971 Preferable examples of the 6-membered ring structure containing from 1-3 hetero atoms are 2,3 or 4-pyridyl, 2 or 3-pyrazinyl, 2,4 or 5-pyrimid1yl, 3 or 4-pyridazinyl, s-triazinyl, 3,4 or 6-as-triazinyl (1,2,3-triazinyl; 1,3,5'-triazinyl; 1,2,4-triazinyl).

Preferred examples of S-membered heterocyclic ring structures containing from 1-4 hetero atoms are:

2 or 3 furyl,

2 or 3 thienyl,

2,3 or 4-thiazolyl,

3 or 4-(1,2,5-thiadiazolyl), 2 or 5-( 1,3,4-thiadiazolyl), 3 or 5-(1,2,4-thiadiazolyl), 2,4 or S-oxazolyl,

3,4 or S-isooxazolyl,

1,2 or 3-pyrrolyl,

1,2 or 4-imidazolyl.

In all the above structures, the R substituent on the heterocyclic nucleus can be in any available position and may be in one or more positions.

Representative compounds of this invention are as follows:

5- Z-thienyl -salicylic acid,

5- Z-pyridyl -salicylic acid, 5-(3-pyridyl)-salicylic acid,

2-hydroxy-5- (4'-pyrimidyl) -benzoic acid, 2-hydroxy-5-(2'-thiazolyl) -benzoic acid.

We have found that the compounds described above have anti-inflammatory activity and are effective in the prevention and inhibition of edema and granuloma tissue formation. In addition, some of them have a useful degree of anti-pyretic and analgesic activity. For these purposes, they are normally administered orally in tablets or capsules, the optimum dosage depending on the particular compound being used and the type and severity of the condition being treated. Although the optimum quantities to be used will depend on the compound employed and the particular type of disease treated, oral dose levels of preferred compounds in the range of 50 mg. to 10 g. per day are useful in the control of said conditions, depend ing on the activity of the specific compound and the reaction sensitivity of the patient.

The compounds of the instant invention are generally prepared by a carboxylation reaction wherein the appropriate starting material is reacted with carbon dioxide, preferably in the presence of potassium carbonate. The reaction is usually carried out in a pressurized vessel at a wide range of temperatures especially from about 50 C. to 200 C., preferably at about C'. at 800 p.s.i. initial pressure. The pressure can also vary from atmospheric pressure on up. The reaction is caried out for a sufficient time to consume the stoichiometric amount of carbon dioxide. When the reaction is complete, the desired product can be isolated by extraction with water, the water layer then acidified and the precipitated product recrystallized.

Various methods for preparing the end products are shown in the following examples. Also, the following examples should be construed as illustrations of the invention and not limitations thereof.

EXAMPLE 1 Preparation of 5-(2-thienyl)-salicylic acid A mixture of 5 g. of 2-(p-hydroxyphenyl)thiophene and 12 g. of anhydrous potassium carbonate in glass lined bomb is heated under a carbon dioxide atmosphere (800 p.s.i. initial pressure) at 175 C. for 8 hours. The material from the bomb is partitioned between water and methylene chloride, and the aqueous layer is acidified.

The precipitated product is dried and recrystallized from benzene/methanol, using charcoal to remove impurities, to obtain pure -(2-thienyl)-salicylic acid.

The preparation of the starting material shown above, namely Z-(p-hydroxyphenyl)-thiophene is shown in I. Gotze (German Pat. 1,051,115).

EXAMPIJE 2 Preparation of 5-(2-pyridyl)-salicylic acid An intimate mixture of 8 g. of 2-(p-hydroxyphenyl) pyridine and 20 g. of anhydrous potassium carbonate is subjected to 800 p.s.i. of carbon dioxide in a glass liner in a pressure bomb, and the temperature raised to 200 C. for 6 hours. Maximum pressure during this time is 1,400 p.s.i. After cooling and venting, the contents of the bomb are taken up in 100 ml. of water and filtered. The filtrate is carefully treated with dilute hydrochloric acid until the pH is 7.5. The precipitated dark brown material is filtered and discarded. Upon careful acidification of the filtrate, the desired product precipitates. It is collected by filtration, taken up in dilute potassium bicarbonate solution and re-precipitated by careful neutralization. The product is recrystallized from methanol, yield 3.8 g., M.P. 266267 C.

The preparation of the starting material used above, namely 5-(2-pyridyl)-salicylic acid is shown in Forsyth and Pyman, J. Chem. Soc. 1926, page 2916.

EXAMPLE 3 Preparation of 5-(3-pyridyl)-salicylic acid An intimate mixture of 1.6 g. of 3-(p-hydroxyphenyl)- pyridine, and 4 g. of anhydrous potassium carbonate is heated in a carbon dioxide atmosphere as described in the previous example. The 5-(3-pyridyl)-salicylic acid recrystallized from dimethyl formamide weighs 0.52 g., M.P. 263-265 C.

i The preparation of the starting material shown above, namely 3-(p-hydroxyphenyl)-pyridine is shown in Forsyth and Pyman, J. Chem. Soc. 1926, page 2916.

EXAMPLE 4 Preparation of 2-hydroxy-5-(4-pyrimidyl)-benzoic acid \A mixture of 5 g. of 4-(p-hydroxyphenyl)pyrimidine (as prepared below) and 12 g. of anhydrous potassium carbonate is heated at 200 C. for 6 hours, under carbon dioxide at an initial pressure of 800 p.s.i. The product is Worked up in the usual way to obtain pure 2-hydroxy- 5-(4'-pyrimidyl)-benzoic acid.

To a stirred solution of 3.0 g. of 4-(p-aminophenyl)- pyrimidine (preparation shown in Lythgoe and Rayner, J. Chem. Soc. 1951, page 2323) in 15 ml. of glacial acetic acid kept at 10-12 C. is added slowly a solution of 1.2 g. of sodium nitrite in 10 ml. of water. After stirring for an additional 0.25 hour, the diazotized solution is poured slowly into a boiling mixture of 10 ml. of concentrated sulfuric acid and 20 ml. of water. The mixture is boiled until a negative coupling test with ot-naphthol solution is obtained. The mixture is cooled, and is neutralized by the gradual addition of sodium bicarbonate, with the addition of more water if necessary to keep the inorganic salts in solution. The crude product is filtered and washed with a little cold water. Recrystallization from benzene/hexane furnishes pure 4-(p-hydroxyphenyl)-pyrimidine.

EXAMPLE 5 Preparation of 2-hydroxy-5-(2'-thiazolyl)- benzoic acid We claim: 1. A compound of the formula:

R2 R1 0 O OH -01; wherein:

R is hydrogen, lower alkyl, lower alkoxy, halogen or haloloweralkyl; and

R is hydrogen, lower alkyl, halo, amino, loweralkylamino, diloweralkylamino, hydroxy or lower alkoxy.

References Cited Prelog et al.: Chem. Abstracts, vol. 41, par. 4133 (1947).

Baine et al.: Chem. Abstracts, vol. 49, par. 4577-78 (1955).

Nandi et al.: Chem. Abstracts, vol. 55, par. 22-219 (1961).

The Merck Index, seventh edition, p. 1444 (1960).

ALAN L. ROTMAN, Primary Examiner US. Cl. X.R. 

